Several genome-wide association studies (GWASs) reported tens of risk genes for alcohol dependence, but most of them have not been replicated or confirmed by functional studies.
The present study used a GWAS to search for novel, functional and replicable risk gene regions for alcohol dependence. Associations of all top-ranked SNPs identified in a discovery sample of 681 African-American (AA) cases with alcohol dependence and 508 AA controls were retested in a primary replication sample of 1,409 European-American (EA) cases and 1,518 EA controls. The replicable associations were then subjected to secondary replication in a sample of 6,438 Australian family subjects. A functional expression quantitative trait locus (eQTL) analysis of these replicable risk SNPs was followed-up in order to explore their cis-acting regulatory effects on gene expression.
We found that within a 90 Mb region around PHF3-PTP4A1 locus in AAs, a linkage disequilibrium (LD) block in PHF3-PTP4A1 formed the only peak associated with alcohol dependence at p,1024. Within this block, 30 SNPs associated with alcohol dependence in AAs (1.661025#p#0.050) were replicated in EAs (1.361023#p#0.038), and 18 of them were also replicated in Australians (1.861023#p#0.048). Most of these risk SNPs had strong cis-acting regulatory effects on PHF3-PTP4A1 mRNA expression across three HapMap samples. The distributions of 2log(p) values for association
and functional signals throughout this LD block were highly consistent across AAs, EAs, Australians and three HapMap samples.
We conclude that the PHF3-PTP4A1 region appears to harbor a causal locus for alcohol
dependence, and proteins encoded by PHF3 and/or PTP4A1 might play a functional role in the disorder.
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